Valeric Acid Suppresses Liver Cancer Development by Acting as a Novel HDAC Inhibitor

Abstract

Liver cancer is the fastest growing cause of cancer deaths in the United States due to its aggressiveness and lack of effective therapies. The current preclinical study examines valeric acid (pentanoic acid [C 5 H 10 O 2 ]), one of the main compounds of valerian root extract, for its therapeutic use in liver cancer treatment. Anticancer efficacy of valeric acid was tested in a series of in vitro assays and orthotopic xenograft mouse models. The molecular target of valeric acid was also predicted, followed by functional confirmation. Valeric acid has a broad spectrum of anticancer activity with specifically high cytotoxicity for liver cancer in cell proliferation, colony formation, wound healing, cell invasion, and 3D spheroid formation assays. Mouse models further demonstrate that systematic administration of lipid-based nanoparticle-encapsulated valeric acid significantly reduces the tumor burden and improves survival rate. Histone deacetylase (HDAC)-inhibiting functions of valeric acid are also revealed by a structural target prediction tool and HDAC activity assay. Further transcriptional profiling and network analyses illustrate that valeric acid affects several cancer-related pathways that may induce apoptosis. In summary, we demonstrate for the first time that valeric acid suppresses liver cancer development by acting as a potential novel HDAC inhibitor, which warrants further investigation on its therapeutic implications.

Selective Targeting of Class I Histone Deacetylases in a Model of Human Osteosarcoma

“…We further provide a molecular basis for treatment-induced apoptosis of OS cells by showing a decrease in well-known anti-apoptosis genes (BCL2L1 and CFLAR/c-FLP) (Figure 8E). This is consistent with previous studies that reported that expression of these two genes can be suppressed by various HDACi in cancer cells [76,78,82,114].…”

Basolateral Secretion from Caco-2 Cells Pretreated with Fecal Waters from Breast Cancer Patients Affects MCF7 Cell Viability

“…In this study, the authors showed that the systemic delivery of these nanoparticles containing valerate demonstrated a reduction of tumor cell proliferation and had a significantly improved survival rate in the studied mouse models. Histone deacetylase (HDAC)-inhibiting functions of valerate were also revealed in this study [ 21 ]. HDAC inhibitors, such as SCFAs, are considered as pro-apoptotic agents.…”

“…The direct effect of this short chain fatty acid has been tested on several cancer lines, including breast cancer cells. Indeed, significant anti-proliferative effects with a positive dose-dependent relationship were observed in all tested cell lines [ 21 ]. Additionally, encapsulated nanoparticles containing valerate were injected via the tail vein into xenograft mouse models of liver tumors to test their effectiveness.…”

“…However, cell death has been detected in liver cancer cells after incubation with valerate. In this study, the pro-apoptotic pathway Bak-1 and Caspase3 was reported to be the main mechanism of action of valerate [ 21 ]. In addition to this pathway, plasma membrane Ca 2+ -ATPase (PMCA) proteins are known to be involved in cell proliferation and apoptosis.…”

Plant Species of Sub-Family Valerianaceae—A Review on Its Effect on the Central Nervous System

“…A specific fraction obtained from V. jatamansi (no data provided about the parts of the plant) significantly inhibited the growth of breast cancer cells in a concentration-dependent manner by inducing apoptosis [ 106 ]. Among its therapeutic effects on insomnia and seizures the valeric acid, which is another active compound in valerian, has been reported to improve immunity against cancer [ 107 ]. Promising data also involve other compounds, in this case, fatty acids naturally occurring in seed oils such as conjugated linolenic acids (CLNs) which are likewise present in C. ruber and V. officinalis) [ 108 ].…”